Sulfatases are members of a highly conserved gene family, sharing extensive sequence homology (Franco, B., et al., Cell, 1995, 81:15-25; Parenti, G., et al., Curr. Opin. Gen. Dev., 1997, 7:386-391), a high degree of structural similarity (Bond, C. S., et al., Structure, 1997, 5:277-289; Lukatela, G., et al., Biochemistry, 1998, 37:3654-64), and a unique post-translational modification that is essential for sulfate ester cleavage (Schmidt, B., et al., Cell, 1995, 82:271-278; Selmer, T., et al., Eur. J. Biochem., 1996, 238:341-345). The post-translational modification involves the oxidation of a conserved cysteine (in eukaryotes) or serine (in certain prokaryotes) residue, at Cβ, yielding L-Cα-formylglycine (a.k.a. FGly; 2-amino-3-oxopropanoic acid) in which an aldehyde group replaces the thiomethyl group of the side chain. The aldehyde is an essential part of the catalytic site of the sulfatase and likely acts as an aldehyde hydrate. One of the geminal hydroxyl groups accepts the sulfate during sulfate ester cleavage leading to the formation of a covalently sulfated enzyme intermediate. The other hydroxyl is required for the subsequent elimination of the sulfate and regeneration of the aldehyde group. This modification occurs in the endoplasmic reticulum during, or shortly after, import of the nascent sulfatase polypeptide and is directed by a short linear sequence surrounding the cysteine (or serine) residue to be modified. This highly conserved sequence is hexapeptide L/V-C(S)-X-P-S-R (SEQ ID NO:32), present in the N-terminal region of all eukaryotic sulfatases and most frequently carries a hydroxyl or thiol group on residue X (Dierks, T., et al., Proc. Natl. Acad. Sci. U. S. A., 1997, 94:11963-11968).
To date thirteen sulfatase genes have been identified in humans. They encode enzymes with different substrate specificity and subcellular localization such as lysosomes, Golgi and ER. Four of these genes, ARSC, ARSD, ARSE, and ARSF, encoding arylsulfatase C, D, E and F, respectively, are located within the same chromosomal region (Xp22.3). They share significant sequence similarity and a nearly identical genomic organization, indicating that they arose from duplication events that occurred recently during evolution (Franco B, et al., Cell, 1995, 81:15-25; Meroni G, et al., Hum Mol Genet, 1996, 5:423-31).
The importance of sulfatases in human metabolism is underscored by the identification of at least eight human monogenic diseases caused by the deficiency of individual sulfatase activities. Most of these conditions are lysosomal storage disorders in which phenotypic consequences derive from the type and tissue distribution of the stored material. Among them are five different types of mucopolysaccharidoses (MPS types II, IIIA, IIID, IVA, and VI) due to deficiencies of sulfatases acting on the catabolism of glycosaminoglycans (Neufeld and Muenzer, 2001, The mucopolysaccharidoses, In The Metabolic and Molecular Bases of Inherited Disease, C. R. Scriver, A. L. Beaudet, W. S. Sly, D. Valle, B. Childs, K. W. Kinzler and B. Vogelstein, eds. New York: Mc Graw-Hill, pp. 3421-3452), and metachromatic leukodystrophy (MLD), which is characterized by the storage of sulfolipids in the central and peripheral nervous systems leading to severe and progressive neurologic deterioration. Two additional human diseases are caused by deficiencies of non-lysosomal sulfatases. These include X-linked ichthyosis, a skin disorder due to steroid sulfatase (STS/ARSC) deficiency, and chondrodysplasia punctata, a disorder affecting bone and cartilage due to arylsulfatase E (ARSE) deficiency. Sulfatases are also implicated in drug-induced human malformation syndromes, such as Warfarin embryopathy, caused by inhibition of ARSE activity due to in utero exposure to warfarin during pregnancy.
In an intriguing human monogenic disorder, multiple sulfatase deficiency (MSD), all sulfatase activities are simultaneously defective. Consequently, the phenotype of this severe multisystemic disease combines the features observed in individual sulfatase deficiencies. Cells from patients with MSD are deficient in sulfatase activities even after transfection with cDNAs encoding human sulfatases, suggesting the presence of a common mechanism required for the activity of all sulfatases (Rommerskirch and von Figura, Proc. Natl. Acad. Sci., USA, 1992, 89:2561-2565). The post-translational modification of sulfatases was found to be defective in one patient with MSD, suggesting that this disorder is caused by a mutation in a gene, or genes, implicated in the cysteine-to-formylglycine conversion machinery (Schmidt, B., et al., Cell, 1995, 82:271-278). In spite of intense biological and medical interest, efforts aimed at the identification of this gene(s) have been hampered by the rarity of MSD patients and consequent lack of suitable familial cases to perform genetic mapping.